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(11) | EP 0 035 374 B1 |
| (12) | EUROPEAN PATENT SPECIFICATION |
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Piperidyl - urea, - thiourea and - guanidine derivatives, and intermediates therefor, processes for preparing them and pharmaceutical compositions containing the derivatives Piperidyl-harnstoff-, -thioharnstoff- und -guanidin-Derivate, ihre Zwischenprodukte, Verfahren zu ihrer Herstellung und die Derivate enthaltende pharmazeutische Zusammensetzungen Dérivés de la pipéridyl-urée, -thiourée et -guanidine, leurs intermédiaires, procédés pour leur préparation et compositions pharmaceutiques les contenant |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
[0001] This invention relates to new piperidine derivatives, to processes for preparing them and to pharmaceutical compositions containing them.
[0002] Piperidylureas are disclosed in the literature possessing a number of pharmacological activities. In French Patent Publication No. 2,387,955 there are disclosed 1-substituted phenyl-3-(piperid-4-yl)urea derivatives possessing major tranquillizing activity. French Patent Publication No. 2,261,008 discloses antihypertensive agents which are 3-aroyl-1-[(4-phenyl-4-oxobutyl)piperid-4-yl]-urea and -thiourea derivatives. French Patent Publication No. 2,287,228 discloses non-narcotic analgesic agents which are inter alia 3-aralkyl-1-alkyl-1-[piperid-4-yl]urea derivatives. In E.P. Publication No. 2886 there is disclosed a narrow group of 1-[1-(indol-3-ylmethyl)piperid-4-yl]-3-benzoyl-(and thenoyl)-ureas and - thioureas possessing psychotropic activity and of value as anti-depressants. This latter group of compounds form part of a larger group of antihypertensive and hypotensive agents.
[0003] We have now found a new class of piperidinyl thioureas and ureas which exhibit pharmaceutical activity especially psychotropic activity in standard pharmacological test procedures, and are potentially useful as anti-depressants. In general the compounds are specific inhibitors of 5-hydroxytryptamine re-uptake in vitro and in vivo, and therefore may also be useful in any other therapeutic applications where such pharmacological specificity may be beneficial.
[0004] The invention provides compounds of formula:
and acid addition and quaternary ammonium salts thereof, wherein the dotted line represents an optional bond, Ar represents a ring system of formula
in which Q is O, S, ―CR7=CR8―, ―N=CR8― and ―N=N―; R4, R5 and R6, and R7 and R8 when present, each represent hydrogen or a substituent selected from halogen, lower alkyl, alkenyl of 2 to 6 carbon atoms, lower alkoxy, NO2, NH2, haloloweralkyl, hydroxyloweralkyl, aminoloweralkyl, mono- or di-loweralkylamino, lower alkylcarbonylamino, ureido, loweralkylsulphonamido, di-loweralkylsulphonyl- amino, lower alkoxycarbonyl, cyano, CONH2 and hydroxy; and additionally either R4 and R5 when adjacent or R6 and R8 when adjacent, together with the carbon atoms to which they are attached also represent a fused five or six membered carbocyclic or heterocyclic ring optionally carrying one or more substituents as defined above; R is an aryl or heteroaryl radical each optionally substituted by one or more substituents as defined above for R4, or R is a cycloalkyl radical containing 5 to 7 carbon atoms; R1, R2, R3 and R9 are each hydrogen or a lower alkyl group; n is 0 or 1; X is =0 or =S; Y is -0- or a direct bond and Z is -CO- or -CH2-, with the provisos that (i) when Ar is unsubstituted phenyl and R9 is hydrogen then Y is -0- and (ii) when Z is -CH2- and Ar represents a phenyl or pyridyl group, either of which may be substituted, then R1 is hydrogen.
[0005] The term 'lower' as used in connection with alkyl or alkoxy groups means that such groups contain 1 to 6 carbon atoms especially 1 to 4 carbon atoms.
[0006] The term "heteroaryl" means a monovalent aromatic heterocyclic group in which the heteroatom is selected from oxygen, nitrogen and sulphur.
[0007] Examples of lower alkyl groups are methyl, ethyl n-propyl, isopropyl, t-butyl, neo-pentyl and n-hexyl. Examples of lower alkoxy groups are methoxy, ethoxy, iso-propoxy, butoxy and hexoxy. Examples of cycloalkyl groups are cyclohexyl and cyclopentyl.
[0008] 'Hydroxyloweralkyl' includes groups such as HO(CH2)m― where m is 1 to 4, e.g. hydroxymethyl or hydroxyethyl.
[0009] Examples of lower alkylamino and di-lower-alkylamino groups are MeNH-, EtNH-, Me2N-, isopropylamino and butylamino.
[0012] 'Aminoalkyl' includes groups such as NH2(CH2)m- where m is 1 to 4, e.g. aminomethyl, aminoethyl.
[0015] Examples of the group Ar when Q is 0 or S are
especially furan-2-yl, thiophen-2-yl, benzo[b]furan-3-yl, benzo[b]thiophen-3-yl.
[0018] When monosubstituted phenyl or pyridyl the group Ar may be for example 4-t-butylphenyl, 4- cumenyl, 4-n-butoxyphenyl, 4-nitrophenyl, 4-dimethylaminophenyl, 3-vinylphenyl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 4-methylpyrid-3-yl, 4-chloropyrid-2-yl, 2-methylpyrid-4-yl or 2-bromopyrid-4-yl. When multi-substituted phenyl or pyridyl the group Ar may be for example 3,4-dichlorophenyl; 3,4,5-trimethylphenyl; 3,4,5-trimethoxyphenyl; 3,4-dichloro-2-methylphenyl; 2,3-diethylphenyl, 3-methyl-4-vinylphenyl, 2,4-dichloropyrid-6-yl, 2,4-dimethylpyrid-6-yl. Examples of Ar when phenyl having a fused 5- or 6-membered carbocyclic or heterocyclic ring are naphth-1-yi; naphth-2-yl; benzo[1,4]dioxan-6-yl; 3,4-methylene-dioxyphenyl; 1,2,3,4-tetrahydronaphth-6-yl; 1,4-dihydronaphth-6-yl; benzo[b]-thiophen-6-yl; indol-6-yl; benzo[b]furan-6-yl; quinol-6-yl and quinol-5-yl. Examples of Ar when pyridyl having a fused 5 or 6 membered carboxylic or heterocyclic ring are quinol-4-yl, quinol-2-yl, 5,6,7,8-tetrahydro-quinol-4-yl or 5,6,7,8-tetrahydro-quinol-2-yl. Examples of such groups when substituted in the fused ring are 6-methoxy-naphth-2-yl, 7-methoxynaphth-2-yl and 4-methylnaphth-2-yl. Preferred fused heterocyclic 'Ar' rings ahve oxygen, nitrogen or sulphur as heteratom(s).
[0019] The group R is exemplified by aryl radicals such as phenyl which can be substituted by the substituents listed for R4, e.g. methyl (such as 4-methyl) ethyl, propyl, nitro (such as 3- or 4-nitro), hydroxy (such as 4-hydroxy), methoxy, ethoxy, fluorine, bromine, or chlorine (such as 3,4-dichloro). Heteroaryl radicals for R include thienyl (e.g. thien-2-yl) i.e. the heteroatom in sulphur, furyl (e.g. fur-2-yl) i.e. the heteroatom is oxygen and pyridyl (e.g. pyrid-2-yl), i.e. the heteroatom is nitrogen, which radicals may be substituted as described above for the phenyl radical Ar.
[0020] Preferred values for Ar are phenyl substituted by one or more alkyl or alkoxy groups of 2 or more carbon atoms, e.g. 4-ethylphenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl; phenyl having a fused 5 or 6 membered carbocyclic ring, e.g. naphth-1-yl, naphth-2-yl, such groups being optionally substituted by lower alkyl, lower alkoxy, halogen, nitro, trifluoromethyl, amino, lower alkylamino (e.g. methyl- amino) diloweralkylamino (e.g. dimethylamino) and cyano.
[0021] Preferably R is phenyl, phenyl substituted by one or more groups selected from halogen, lower alkyl, lower alkoxy, hydroxy or nitro, or a thienyl or pyridyl group.
[0023] Preferably Z is -CO- and R is phenyl or phenyl substituted in the 4-position by lower alkoxy, e.g. methoxy.
[0027] Preferred compounds of the invention are
1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(naphth-1-ylmethyl)piperid-4-yl]urea;
1 -benzoyl-3-[1-(4-isopropylbenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(5,6,7,8-tetrahydronaphth-2-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(3,4-dimethylbenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(indan-5-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(1-naphth-2-yl)piperid-4-yl]urea; and
1 -benzoyl-3-[-(4-ethylbenzyl)piperid-4-yl]urea.
[0028] Examples of acid addition salts are those formed from inorganic and organic acids and in particular pharmaceutically acceptable acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, sulphonate (such as the methanesulphonate and p-toluenesulphonate), acetate, maleate, citrate, fumarate, tartrate, malonate and formate.
[0029] Compounds of formula I were tested for psychotropic activity by their ability to inhibit p-chloroamphetamine (pCA) induced hyperactivity and/or by their ability to inhibit 5-hydroxytryptamine (5-HT) uptake in brain slices.
[0030] The following test procedure was used to test for ability to inhibit p-chloroamphetamine induced hyperactivity;
[0031] Three groups of 4 female mice (20-24 g) receive the test compounds (50 mg/kg po) and a fourth group the requisite volume of vehicle. Thirty minutes later all the animals are given 20 mg/kg p-chloroamphetamine (pCA) ip. The grouped mice are placed immediately in square plastic cages in activity monitors and their motor activity recorded over the period 10-30 minutes post pCA. This procedure is repeated three more times so that four groups of mice are used per treatment and each activity monitor is used with all treatments in turn. The inhibition of pCA induced hyperactivity is calculated thus:-
where C = mean activity of control groups 10-30 minutes post pCA.
T = mean activity of treated groups 10-30 minutes post pCA.
[0032] This test is used as an in vivo screen for detection of 5-hydroxytryptamine uptake inhibitors.
[0033] Compounds giving >50% inhibition are considered of special interest. In such a test the following compounds were particularly active:
Compounds of formula I were tested for ability to inhibit 5-hydroxytryptamine (5-HT) uptake in brain slices using the following procedure:
The effects of test compound on the neuronal uptake of 5-hydroxytryptamine into slices
of cerebral cortex prepared from rat brain is determined according to the method described
by Snyder, Green and Hendley, Kinetics of H3-norepinephrine accumulation into slices from different regions of the rat brain (J.
Pharm. exp. Therap. 164: 90-102) (1968). Concentration-response curves for the test
compound and for the standard agent, imipramine, are obtained. The potency of the
test compound is expressed in proportion to that of imipramine. Thus, the potency
ratio for the test compound -
Compounds not achieving 50% inhibition are considered inactive.
[0034] In such a test the compound 1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea above was particularly active having a potency ratio of 8.8 (imipramine = 1.0).
[0035] In vivo 5-HT uptake inhibition was also demonstrated for compounds of the invention by a procedure involving 5-hydroxy-L-tryptophan (5-HTP) induced behavioural syndrome. Mice given a high dose of 5-HTP exhibit a behavioural syndrome consisting of tremor, hind limb abduction, lateral head weaving and forepaw treading. In addition to these signs rats also exhibit head twitching and circling behaviour. In the following experiments the syndrome was said to be present if mice exhibited at least 3 and rats at least 4 of these signs. When animals are given a low dose of 5-HTP, which does not itself produce the syndrome, it can be produced by pretreatment with 5-HT uptake inhibitors.
Thus, this test can be used as an indication of in vivo uptake inhibition.
a) Dose/response study in mice
[0036] Groups of 12 (2 subgroups of 6) female mice (18-22 g) were used per dose, each group being housed in a separate cage for the duration of the experiment. Mice were dosed p.o. with either test compound or vehicle (0.5% HPMC) and 30 minutes later received a threshold dose of 5-HTP (80 mg/kg i.p.) and were placed in perspex cylinders (12" diameter). After a further 20 minutes the mice were observed for 5 minutes for the presence or absence of the syndrome. The dose that produced the syndrome in 50% of the mice was calculated using the method of Litchfield and Wilcoxon, J. Pharm. Exp. Ther. 96, 99-113 (1949).
b) Dose/Response study in rats
[0037] Groups of 6 male rats (150g) were dosed with test compound suspended in HPMC. Thirty minutes later 5-HTP (70 mg/kg i.p.) was given and the number of signs/rat recorded between 20 and 35 minutes post 5-HTP. Linear regression analysis of the results was performed and the ED50 calculated from this.
[0038] The results found for 1-benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (A) and for the antidepressant clomipramine are shown below:
[0039] This invention also provides processes for preparing compounds of formula I or acid addition or quaternary ammonium salts thereof. In general the compounds of formula I are prepared by building up the molecule from the appropriate starting materials by known reactions. Accordingly a first process for preparing a compound of formula I comprises reacting a compound of formula II
wherein the dotted line, R, R1, R3, Z and X are as defined in connection with formula I, with a compound of formula III
wherein Ar, Y, n, R2 and R9 are as defined above and W represents a leaving group; such as halogen, (e.g. chlorine, bromine or iodine), an organic sulphonyloxy radical (e.g. tosyloxy, mesyloxy), or a radical of formula
i.e. a sulphate.
[0040] The reaction is preferably carried out in the presence of base, e.g. potassium carbonate, triethylamine; otherwise the reaction may be carried out by heating in the presence of an inert solvent, e.g. toluene.
[0041] A second general process for preparing compounds of formula I wherein X is 0 or S and R3 is hydrogen comprises reacting a compound of formula
wherein Ar, Y, R1, R2, R9 and n are as hereinbefore defined with a compound of formula
wherein R and Z are as hereinbefore defined and X is 0 or S. Such a reaction can be effected at room temperature. The starting materials of formula (IV) wherein R1 is hydrogen may be prepared by methods described in our U.K. Patent Specification No. 1,345,872. The starting materials of formula IV wherein R1 is lower alkyl may be prepared by alkylating corresponding compounds of formula IV wherein R1 is hydrogen, or by methods analogous to those described in Specification No. 1,345,872.
[0042] A further process for preparing compounds of formula I comprises reacting a compound of formula IV as defined hereinbefore with a compound of formula
wherein R, R3 and Z are as defined above and X is as defined above and if desired converting the product to an acid addition salt.
[0043] This process may be performed in the absence of solvent but is usually carried out by heating the reactants in the presence of a suitable inert organic solvent, for example toluene, pyridine, xylene, chlorobenzene, dimethylformamide or dioxan. Pyridine is the preferred solvent. Often it is convenient to reflux the reactants in the solvent until the reaction is complete. High yields e.g. 80-90% can be obtained. Preferably the solvent has a boiling point greater than 100°C.
[0045] A still further process for preparing compounds of formula I as hereinbefore defined wherein Z is -CO- comprises acylating a compound of formula
wherein the dotted line, Ar, X, Y, R2, R3, R9, n and R1 are as hereinbefore defined with an acylating agent containing the group -COR. Examples of acylating agents are reactive derivatives of acids of formula RCOOH such as the acid halides (e.g. chloride, bromide) and the anhydride and activated esters as used in peptide chemistry. Other methods of acylation are well known in the art such as those employing coupling agents such as carbodiimides, e.g. dicyclohexylcarbodiimide.
[0046] Compounds of formula VI may be prepared by hydrolysis of compounds of formula I wherein Z is ―CO―.
[0047] Compounds of formula I may also be prepared by reducing a compound of formula VII or VIII
in which formulae Z, X, Ar, Y, n, R, R1, R2, R3 and R9 are as hereinbefore defined and Be represents an anion, e.g. a halide ion. For example catalytic hydrogenation when X = 0, e.g. in the presence of Raney nickel or platinum catalyst gives piperidine compounds of formula I. The reduction may also be effected by a process described and claimed in our U.K. Patent Specification No. 1542137. Such a reduction process employs an alkali metal borohydride in a secondary alkanol having 3-5 carbon atoms, e.g. isopropanol. Alternatively reduction of compounds of formula VIII using an alkali metal borohydride in methanol gives dehydropiperidine compounds of formula I.
[0048] Yet a further process for preparing a compound of formula I comprises reacting a compound of formula
wherein Ar, Y, n, R2 and R9 are as hereinbefore defined with a compound of formula II, when X = 0, in the presence of a catalyst, e.g. a nickel catalyst such as Raney nickel.
[0049] Compounds of formula I wherein X is =0 may also be prepared by treating a corresponding compound of formula (X)
wherein the dotted line Ar, Y, R, R1, R2, R3, R9 and Be are as hereinbefore defined, n is 1 and R10 is an organic quaternizing group which can be removed under mild conditions, e.g. by hydrogenolysis, that do not affect the rest of the molecule. For example, when R10 is an arylmethyl radical, such as benzyl, hydrogenolysis under standard conditions, e.g. using an appropriate catalyst such as a palladium on carbon, platinum or nickel catalyst, gives compounds of formula I. Methods for effecting this reaction are given in our U.K. Patent Specification No. 1,399,608. Suitably solvents include alkanols such as methanol.
[0050] Starting materials of formula X may be prepared by reacting a compound of formula III as defined above with a compound of formula
wherein R10, R3, R1 and R are as herein defined and X is =0.
[0051] Compounds of formula I wherein Y is -0- may also be prepared by reacting a compound of formula
wherein hal represents halogen and the dotted line R, R1, R2, R3, R9, n, X and Z are as hereinbefore defined with a compound of formula
wherein Ar is as hereinbefore defined. This reaction is conveniently carried out by heating reactants in an inert solvent such as dimethylsulphoxide, in the presence of base, e.g. sodium hydride. Preferably hal represents bromine or chlorine.
[0052] Once a compound of formula I having a reactive substituent group has been prepared then that compound may be converted in known manner to other compounds of formula I. For example when Ar is a group having a lower alkoxy or aryl lower alkoxy substituent on an aromatic ring dealkylation produces a corresponding compound of formula I wherein Ar carries a hydroxy substituent. When Ar is a group having nitro on an aromatic ring then reduction (e.g. catalytic hydrogenation) can convert the nitro group to an amino group. Such amino groups may be acylated.
[0053] The aforementioned processes may also include the step of conversion of an acid addition salt into the free base form or vice versa. Quaternisation of the tertiary nitrogen of the piperidine ring may be included as an optional after step, e.g. using alkyl or aryl lower alkyl halides, e.g. methyl iodide, benzyl chloride.
[0054] Starting materials used in the above mentioned processes are known compounds or may be prepared by analogous processes. For example, a compound of formula II wherein X=O may be prepared by reducing the corresponding compound of formula (XIV)
using for example catalytic hydrogenation. Compounds of formula XIV wherein R3 is H and X is 0 or S may be prepared by reacting a 4-aminopyridine with a compound of formula RZNCX. Compounds of formula I or XIV wherein Z is -CO- and R3 is lower alkyl may be prepared by alkylating a corresponding compound of formula I or XIV wherein R3 is hydrogen (e.g. using an alkali metal hydride and an alkyl halide).
[0055] Compounds of formula VIII may be prepared by reacting a compound of formula III wherein W is halogen, especially bromine, with a compound of formula XIV.
[0056] Two general reactions for preparing starting materials of formula II are illustrated in the scheme below:
[0057] If necessary, in any of the reactions herein described, reactive substituent groups may be blocked during a reaction and released at a later stage. For example an amino substituent may be protected by a benzyloxy-carbonyl group which is removable using H2/Pd at the end of a reaction. Dehydropiperidine compounds of formula I (in which the optional bond is present) are also useful as intermediates for preparing the piperidines of formula I, being converted by reduction. Acylurea compounds of formula I are also useful as intermediates for preparing other acylurea compounds of formula I, by hydrolysing to give the urea of formula VI and re-acylating.
[0058] This invention also includes pharmaceutical compositions containing as active ingredient an active compound mf formula I as above defined. The active compound may be finely comminuted if desired. In addition to the active ingredient, the compositions also contain a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders, or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient.
[0059] Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly cachets are included.
[0060] Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterile organic solvent or a mixture of both. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too insoluble for this it can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. In other instances composition can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilised by intramuscular, intraperitoneal or subcutaneous injection. In many instances, a compound is orally active and can be administered orally either in liquid or solid composition form.
[0061] Preferably the pharmaceutical composition is in unit dosage form. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredients; the unit dosage form can be a packaged composition, the package containing specific quantities of composition, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in package form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 5 mg or less to 500 or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.
[0062] Accordingly this invention also provides a process for producing a pharmaceutical composition exhibiting psychotropic activity characterised in that a compound of formula I as defined in Claim 1 or an acid addition or quaternary ammonium salt thereof is brought into association or combination with a pharmaceutically acceptable carrier.
[0063] The amount of compound used will depend on the compound employed, the severity and nature of the depression and the animal being treated. With large animals (about 70 kg body weight) by the oral route the dose is preferably from about 5 to about 75 mg and most preferably from about 10 to 25 mg every four hours or as needed. By the parenteral route the dosage is preferably from about 2 to about 35 mg as needed. Ideally therapy should be initiated with lower dosages, the dosage thereafter being increased until the desired anti-depressive effect is obtained.
Example 1
1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea
[0065] 4-Benzoylureidopiperidine (1.28 g, 0.005 m), 2-(bromomethyl)naphthalene (1.1 g, 0.005 m) and triethylamine (0.6 g, 0.006 m) in dimethylformamide (25 cm3) were stirred at room temperature for 23 hours. Water was added and the precipitated solid filtered off and washed well with water. The solid was suspended in warm ethanol, acidified with ethanolic HCI and then heated until all the solid had dissolved. The title compound crystallised and was collected as the hydrochloride salt, hemihydrate (1.6 g), m.p. 232-234°C.
Example 2
1-Benzoyl-3-[1-(naphth-1-ylmethyl)piperid-4-yl]urea
[0067] 1-Chlormethylnaphthalene (0.88 g, 0.005 m), 4-benzoylureidopiperidine (1.28 g, 0.005 m) and triethylamine (0.6 g) in dimethylformamide (25 cm3) were stirred at room temperature for 24 hours. Water was added and the precipitated solid filtered off. The solid was suspended in isopropylalcohol and acidified with ethanolic HCI. The title compound was filtered off and dried as the hydrochloride salt, hemihydrate (1.2 g), m.p. 185-186°C.
Example 3
1-Benzoyl-3-[1-(4-isopropylbenzyl)piperid-4-yl]urea
[0069] 4-Isopropylbenzyl chloride (0.84 g, 0.005 m), 4-benzoylureidopiperidine (1.28 g, 0.005 m) and triethylamine (0.6 g) in dimethylformamide (25 cm3) were stirred at room temperature for 24 hours. Water was added and the precipitated solid filtered off. The solid was suspended in isopropylalcohol and acified with ethanolic HCI. The title compound was filtered off and dried (1.2 g), m.p. 240-242°C as the hydrochloride salt, hemihydrate.
Example 4
1-Benzoyl-3-[1-(6-methoxynaphth-2-ylmethyl)piperid-4-yl]urea
[0071] 6-Methoxynaphth-2-ylmethanol (0.94 g, 0.005 m) in dry benzene (10 cm3) was refluxed with thionyl chloride (3 cm3) for 3 hours. The solvent was evaporated and the residue treated with benzene (3x) and evaporated. 4-Benzoylureidopiperidine (1.28 g, 0.005 m), triethylamine (1.5 g, 0.015 m) and dimethylformamide (25 cm3) was added to the residue and the reaction mixture stirred at 50°C for 2 hours. The solution was filtered and then diluted with water. The precipitated solid was washed with water, dissolved in chloroform and the chloroform extract washed with water and dried (MgS04). Evaporation gave a solid which was suspended in ethanol, acidified with ethanolic HCI and heated until all the solid had dissolved. On cooling the title compound crystallised and was filtered and dried as the hydrochloride, hemihydrate (1.3 g), m.p. 243-244°C.
Example 5
3-Benzoyl-1-[1-(1,4-benzodioxan-6-ylmethyl)piperid-4-yl]urea
[0072] 1,4-Benzodioxan-6-ylmethanol (1.55 g, 9.34 mmol) and thionyl chloride (1.7 g, 14.29 mmol) were refluxed in sodium-dried diethyl ether (30 cm3) for 3 hours then the solvent and excess thionyl chloride evaporated. The residue was dissolved in toluene (20 cm3), thionly chloride (1.7 g, 14.29 mmol) was added and the solution heated and stirred at 80°C for 3 hours. Evaporation of the solvent gave a residue. 4-Benzoylureidopiperidine (2.0 g, 8.1 mmol) and triethylamine (1.09 g, 10 mmol) were added to the residue and refluxed in isopropyl alcohol overnight. The isopropyl alcohol was evaporated and the residue triturated with water. The water was decanted and the residue crystallised from isopropyl alcohol (1.64 g).
[0073] The. base was suspended in refluxing isopropyl alcohol, ethanolic HCI was added and the mixture filtered. The filtrate was cooled at 5°C overnight and the title compound collected and dried as the hydrochloride, quaterhydrate (1.46 g), m.p. 231-235°C.
Example 6
1-Benzoyl-3-[1-(3,4-dimethylbenzyl)piperid-4-yl]urea
[0074] 3,4-Dimethylbenzyl alcohol (0.68 g, 0.005 m) in dry benzene (10 cm3) was treated with thionyl chlorde (3 cm3) and refluxed for 3 hours. The solvent was evaporated and the residue treated with benzene (3 times) and evaporated. 4-Benzoylureidopiperidine (1.28 g, 0.05 m), triethylamine (1.5 g, 0.015 m) and dimethylformamide (25 cm3) were added to the residue and the reaction mixture stirred at 50°C for 2 hours. The solution was filtered and the filtrate diluted with water. The precipitated solid was filtered, dissolved in chloroform and washed well with water, dried (MgS04) and evaporated to give a solid. The solid was suspended in ethanol and acidified with ethanolic HCI to give the title compound, which was recrystallised from ethanol as the hydrochloride, quaterhydrate, m.p. 239-240°C.
Example 7
1-Benzoyl-3-[1-(3-aminobenzyl)piperid-4-yl]urea
[0076] 1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea 4.47 g (from Example 13) was hydrogenated with 5% Pd/C (0.5 g) at atmospheric pressure and room temperature until no more hydrogen was taken up. The catalyst was filtered and the filtrate evaporated. The residue was dissolved in water and basified with .880 ammonia. The precipitated solid was filtered, washed well with water, dried, treated with charcoal, and evaporated to give the title compound, (1.9 gms). This was recrystallised from ethanolic HCI to give the dihydrochloride salt, monohydrate, m.p. 194-195°C.
Example 8
1-Benzoyl-3-[1-(3-dimethanesulphonylaminobenzyl)piperid-4-yl]urea
[0077] Methanesulphonyl chloride (0.55 g) was added at room temperature to a stirred solution of the product of Example 7 (1.69 g) and triethylamine (0.5 g) in chloroform (10 cm3). After addition was complete the solution was allowed to stir for 3 hours, then washed with water, dried, and evaporated. The residue was purified by trituration with ethanol at reflux. The product was suspended in ethanol, acidified with ethanolic HCI, heated for 5 minutes, cooled, and the title hydrochloride collected by filtration (0.5 g), m.p. 189-91 °C.
Examples 9 to 35
[0078] Using the procedure of Example 1 the following compound of formula I are obtained by reacting the appropriate compound of formula III wherein W is chlorine or bromine with 4-benzoylureidopiperidine:
Example 36
1-Benzoyl-3-[1 -(naphth-2-ylmethyl)piperid-4-yl]thiourea
[0079] 4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0042 m) and benzoylisothiocyanate (0.69 g, 0.0042 m) in toluene (120 cm3) was stirred at room temperature for 6 hours. The solvent was evaporated and the gum dissolved in isopropyl alcohol and acidified with ethanolic HCI. The solvent was evaporated and the residue dissolved in ethyl acetate. The title compound crystallised and was filtered and dried as the monohydrochloride quarterhydrate salt, m.p. 212-214°C.
Example 37
1 -[1 -(Naphth-2-ylmethyl)piperid-4-yl]-3-(then-2-oyl)urea
[0080] 4-Amino-1(naphth-2-ylmethyl)piperidine (1.0g, 0.0047 m) and 1-(then-2-oyl)urea (0.65 g, 0.0042 m) in pyridine (5 cm3) was refluxed for 9.5 hours. The solvent was evaporated, water added, and the precipitated title compound filtered and washed well with water. This was recrystallised from ethanol, converted to the hydrochloride salt in ethanol with ethanolic HCI, and recrystallised from ethanol, 0.5 g, at the hydrochloride, m.p. 217-219°C.
Examples 38-41
[0081] Using a procedure analogous tp Example 37 4-amino-1-(naphth-2-ylmethyl)piperidine is reacted with each of the following ureas:
3,4-dimethylbenzoylurea,
3-trifluoromethylbenzoylurea,
4-nitrobenzoylurea and
1-(pyrid-4-oyl)urea to give the following compounds:
Example 42
1-(4-Methoxybenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea
[0082] 1-Benzoyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (prepared according to Example 1) is hydrolysed by refluxing in 2N sodium hydroxide to give [1-(naphth-2-ylmethyl)piperid-4-yl]urea (m.p. 183-5°C). The product is acylated by reaction with 4-methoxybenzoyl chloride to give the title compound, m.p. of HCI, quarterhydrate = 193-193.5°C).
Examples 43-44
[0083] In a manner analogous to Example 1, 2-bromomethylnaphthalene was reacted with the following compounds of formula II:
4-benzylureidopiperidine,
4-(p-fluorobenzoyl)ureidopiperidine to give the following compounds of formula I:
Examples 45-53
[0084] Using a procedure analogous to Example 1, 4-benzoylureidopiperidine is reacted with the following compounds:
2-(naphth-2-yl)ethyl tosylate,
6-cyanonaphth-2-ylmethyl bromide,
6-fluoronaphth-2-ylmethyl bromide,
6-bromonaphth-2-ylmethyl bromide,
1-(naphth-2-yl)propyl chloride,
di-(naphth-2-ylmethyl)sulphate,
6-chloromethylquinoxaline,
3-chloromethylcinnoline,
6-chloromethylisoquinoline,
to give the following compounds.
Example 54
1-Benzoyl-3-[ 1-(naphth-2-ylmethyl)piperid-4-yl]urea
[0085] 2-Bromomethylnaphthalene is heated with 4-benzoylureidopyridine in acetonitrile solvent to give 1-benzoyl-3-[1-(naphth-2-ylmethyl)-4-pyridinium urea bromide m.p. 247―8°C, This compound is reduced by refluxing with sodium borohydride in isopropyl alcohol solvent to give the title compound, m.p. of HCl hemihydrate salt = 232―234°C.
[0086] Alternatively 1-benzoyl-3-[1-(naphth-2-ylmethyl)-4-pyridinium]urea bromide is reduced with sodium borohydride in methanol solvent to give 1-benzoyl-3-[1-(naphth-2-ylmethyl)-3,4-dehydro- piperid-4-yl]urea. This compound may then be reduced by refluxing with sodium borohydride in isopropyl alcohol to give the title compound.
Example 55
1-Benzoyl-1-methyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea
[0087] 1-Methyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (1.4 g) (prepared by reacting 4-amino-1-(naphth-2-ylmethyl)piperidine with methyl isocyanate) in toluene (30 cm3) was acylated using benzoyl chloride (0.92 g) in presence of pyridine (0.6 g) to give the title compound: m.p. of HCI, hemihydrate salt = 164-166°C.
Example 56
1-Benzoyl-3-methyl-3-[1 -(naphth-2-ylmethyl)piperid-4-yl]urea
and acid addition and quaternary ammonium salts thereof, in which the dotted line represents an optional bond, Ar represents a ring system of formula
in which Q is O, S, ―CR7=CR8―, ―N=CR8― and ―N=N―; R4, R5 and R6, and R7 and R8 when present, each represent hydrogen or a substituent selected from halogen, lower alkyl, alkenyl of 2 to 6 carbon atoms, lower alkoxy, N02, NH2, halolower alkyl, hydroxylower alkyl, aminolower alkyl, mono- or diloweralkylamino, lower alkylcarbnonylamino, ureido, lower alkylsulphonamido, di-loweralkyl- sulphonyl amino, lower alkoxycarbonyl, cyano, CONH2 and hydroxy; and additionally either R4 and R5 when adjacent or R6 and R8 when adjacent, together with the carbon atoms to which they are attached also represent a fused five or six membered carbocyclic or heterocyclic ring optionally carrying one or more substituents as defined above; R is an aryl or heteroaryl radical each optionally substituted by one or more substituents as defined above for R4, or R is a cycloalkyl radical containing 5 to 7 carbon atoms; R1, R2, R3 and R9 are each hydrogen or a lower alkyl group; n is 0 or 1; X is =0 =S; Y is -0- or a direct bond and Z is -CO- or -CH2-, the term 'lower' used to qualify alkyl or alkoxy means such groups containing 1 to 6 carbon atoms, and the term "heteroaryl" means a monovalent aromatic heterocyclic group in which the heteroatom is selected from oxygen; nitrogen and sulphur; with the provisos that (i) when Ar is unsubstitued phenyl and R9 is hydrogen then Y is -0-, and (ii) when Z represents ―CH2― and Ar represents a phenyl or pyridyl group, either of which may be substituted, then R1 is hydrogen.
1-benzoyl-3-[1-(naphth-1-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(4-isopropylbenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(5,6,7,8-tetrahydronaphth-2-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(3,4-dimethylbenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(indan-5-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-{ 1-[1-(naphth-2-yl)ethyl]-piperid-4-yl}urea;
1-benzoyl-3-[1-(4-ethylbenzyl)piperid-4-yl]urea;
3-benzoyl-1-[1-(1,4-benzodioxan-6-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(6-methoxynaphth-2-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(2-[naphth-1-yloxy]ethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(3,4-dibromobenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(4-n-propoxybenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(2-[naphth-2-yl]ethyl)piperid-4-yl]urea;
1-benzoyl-3-[1 -(1 -[naphth-2-yl]propyl)piperid-4-yl]urea
or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.
1-(3,4-dimethylbenzoyl)-3-[1 -(naphth-2-ylmethyl)piperid-4-yl]urea;
1-(4-methoxybenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea;
1-(4-fluorobenzoyl)-3-[1 -(naphth-2-ylmethyl)piperid-4-yl]urea; and
1-(4-nitrobenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea
or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.
a) a compound formula II
is reacted with a compound of formula III
in which formulae the dotted line, n, Ar, X, Y, Z, R, R1, R2, R3 and R9 are as defined in Claim 1 and W represents a leaving group; or
b) a compound of formula (IV)
is reacted with a compound of formula
in which formulae n, Ar, Y, Z, R, R1, R2 and R9 are as defined in Claim 1 and X is 0 or S to give a corresponding compound of formula
I wherein R3 is hydrogen, or
c) a compound of formula IV as defined above is reacted with a compound of formula
wherein X is 0 or S and R, R3 and Z are as defined in Claim 1, or
d) a compound of formula VI
wherein n, Ar, X, Y, R1, R2, R3 and R9 are as defined in Claim 1 is acylated with an acylating agent containing the group
-COR to give a corresponding compound of formula I in which Z is -CO-, or
e) a compound of formula VII or VIII or
wherein n, Ar, X, Y, Z, R, R1, R2, R3 and R9 are as defined in Claim 1 and B- is an anion, is reduced, or
f) a compound of formula IX
where n, Ar, Y, R2 and R9 are as defined in Claim 1 is reacted with a compound of formula II as defined hereinabove
wherein X is 0 in the presence of a nickel catalyst, or
g) a compound of formula X
wherein the dotted line, Ar, Y, Z, R, R1, R2 and R3 are as defined in Claim 1 and B is an anion, X is =0, n is 1 and R10 is an organic quaternising group, is treated under conditions suitable to remove
the group R10 to give a corresponding compound of formula I or
h) a compound of formula XII
wherein the dotted line, n, R, R1, R2, R3, R9, X and Z are as defined in Claim 1 and hal represents halogen, is reacted with a
compound of formula:
wherein Ar is as defined in Claim 1 to give a compound of formula I wherein Y is -0-,
or
i) a compound of formula I having a reactive substituent group is converted to a compound of formula I having a different substituent group, or
j) a basic compound of formula I is converted to an acid addition or quaternary ammonium salt or an acid addition salt of a compound of formula I is converted to the free base form.
and acid addition and quaternary ammonium salts thereof, in which the dotted line represents an optional bond, Ar represents a ring system of formula
in which Q is O, S, ―CR7=CR8―, ―N=CR8― and ―N=N―; R4, R5 and R6, and R7 and R8 when present, each represent hydrogen or a substituent selected from halogen, lower alkyl, alkenyl of 2 to 6 carbon atoms, lower alkoxy, N02, NH2, haloloweralkyl, hydroxyloweralkyl, aminoloweralkyl, mono- or diloweralkylamino, lower alkylcarbonylamino, ureido, lower alkylsulphonamido, diloweralkyl- sulphonylamino, lower alkoxycarbonyl, cyano, CONH2 and hydroxy; and additionally either R4 and R5 when adjacent or R6 and R8 when adjacent, together with the carbon atoms to which they are attached also represent a fused five or six membered carbocyclic or heterocyclic ring optionally carrying one or more substituents as defined above; R is an aryl or heteroaryl radical each optionally substituted by one or more substituents as defined above for R4, or R is a cycloalkyl radical containing 5 to 7 carbon atoms; R1, R2, R3 and R9 are each hydrogen or a lower alkyl group; n is 0 or 1; X is =O or =S; Y is ―O― or a direct bond and Z is ―CO― or ―CH2―, the term 'lower' used to qualify alkyl or alkoxy means such groups containing 1 to 6 carbon atoms and the term "heteroaryl" means a monovalent aromatic heterocyclic group in which the heteroatom is selected from oxygen; nitrogen and sulphur; with the provisos (i) that when Ar is unsubstitued phenyl and R9 is hydrogen then Y is -0-, and (ii) when Z represents ―CH2― and Ar represents a phenyl or pyridyl group, either of which may be substituted, then R1 is hydrogen characterised in that
a) a compound formula II
is reacted with a compound of formula III
in which formulae the dotted line, n, Ar, X, Y, Z, R, R1, R2, R3 and R9 are as defined hereinabove and W represents a leaving group; or
b) a compound of formula (IV)
is reacted with a compound of formula in which formulae n, Ar, Y, Z, R, R1, R2 and R9 are as defined above and X is O or S to give a corresponding compound of formula
I wherein R3 is hydrogen, or
c) a compound of formula IV as defined above is reacted with a compound of formula
wherein X is 0 or S and R, R3 and Z are as defined hereinabove, or
d) a compound of formula VI
wherein n, Ar, X, Y, R1, R2, R3 and R9 are as defined hereinabove is acylated with an acylating agent containing the group
-COR to give a corresponding compound of formula I in which Z is -CO-, or
e) a compound of formula VII or VIII
or
wherein n, Ar, X, Y, Z, R, R1, R2, R3 and R9 are as defined hereinabove and B⊖ is an anion, is reduced, or
f) a compound of formula IX
where n, Ar, Y, R2 and R9 are as hereinabove defined is reacted with a compound of formula II as defined hereinabove
wherein X is 0 in the presence of a nickel catalyst, or
g) a compound of formula X
wherein Ar, Y, Z, R, R1, R2, R3 and B are as hereinbefore defined, X is =0, n is 1 and R10 is an organic quaternizing group, is treated under conditions suitable to remove
the group R10 to give a corresponding compound of formula I or
h) a compound of formula XII
wherein the dotted lines, n, R, R1, R2, R3, R9, X and Z are as defined hereinabove and hal represents halogen, is reacted with a
compound of formula:
wherein Ar is as hereinbefore defined to give a compound of formula I wherein Y is
-0-, or
i) a compound of formula I having a reactive substituent group is converted to a compound of formula I having a different substituent group, or
j) a basic compound of formula I is converted to an acid addition or quaternary ammonium salt or an acid addition salt of a compound of formula I is converted to the free base form.
1-benzoyl-3-[1-(naphth-1-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(4-isopropylbenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(5,6,7,8-tetrahydronaphth-2-ylmethyl)piperid-4-yl]urea;
1-benzoyt-3-[1-(3,4-dimethylbenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(indan-5-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-{ 1-[1 -(naphth-2-yl)ethyl]-piperid-4-yl}urea;
1-benzoyl-3-[1-(4-ethylbenzyl)piperid-4-yl]urea;
3-benzoyl-1-[1-(1,4-benzodioxan-6-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(6-methoxynaphth-2-ylmethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(2-[naphth-1-yloxy]ethyl)piperid-4-yl]urea;
1-benzoyl-3-[1-13,4-dibromobenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(4-n-propoxybenzyl)piperid-4-yl]urea;
1-benzoyl-3-[1-(2-[naphth-2-yl]ethyl)piperid-4-yl]urea; or
1-benzoyl-3-[1-( 1-[naphth-2-yl]propyl)piperid-4-yl]urea.
1-(3,4-dimethylbenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea;
1-(4-methoxybenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea;
1-(4-fluorobenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea; and
1-(4-nitrobenzoyl)-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea
or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.
und deren Säureadditions- und quaternäre Ammoniumsalze, worin die strichlierte Linie eine gegebenenfalls vorhandene Bindung darstellt, Ar ein Ringsystem der Formel
ist, worin Q die Bedeutung O, S, -CR'=CR8-, -N=CR8- und N=N- hat; R4, R5 und R7 sowie R7 und R8, wenn vorhanden jeweils Wasserstoff oder ein Substituent ausgewählt aus Halogen, nied.Alkyl, Alkenyl mit 2 bis 6 C-Atomen, nied.Alkoxy, NO2, NH2, Halogen-nied.alkyl, Hydroxy-nied.alkyl, Amino-nied.- alkyl, Mono- oder Di-nied.alkylamino, nied.Alkylcarbonylamino, Ureido, nied.Alkylsulfonamido, Di-nied.- alkylsulfonylamino, nied.Alkoxycarbonyl, Cyano, CONH2 und Hydroxy sind; und weiterhin entweder R4 und R5, wenn sie benachbart sind, oder R6 und R8, wenn sie benachbart sind, zusammen mit den C-Atomen, an die sie gebunden sind, auch einen kondensierten 5-oder 6-gliedrigen carbocyclischen oder heterocyclischen Ring bilden, der gegebenenfalls einen oder mehreren Substituenten, wie oben definiert, trägt; R ein Aryl- oder Heteroarylrest ist, jeweils gegebenenfalls substituiert durch einen oder mehrere Substituenten, wie oben für R4 definiert, oder R einen Cycloalkylrest mit 5 bis 7 C-Atomen darstellt; R1, R2, R3 und R9 jeweils Wasserstoff oder nied.Alkyl bedeuten; n=Null oder 1 ist; X =0 oder =S darstellt; Y ―O― oder eine Direktbindung bedeutet und Z ―CO― oder ―CH2― ist, wobei der Ausdruck "nied.", der für Alkyl oder Alkoxy verwendet wird, bedeutet, daß derartige Gruppen 1 bis 6 C-Atome enthalten und der Ausdruck "Heteroaryl" eine einwertige aromatische heterocyclische Gruppe bezeichnet, in der das Heteroatom aus Sauerstoff, Stickstoff und Schwefel ausgewählt ist; mit den Maßgaben, daß, (i) wenn Ar unsubstituiertes Phenyl ist und R9 Wasserstoff darstellt, Y -0- ist, und (ii) wenn Z ―CH2― ist und Ar eine Phenyl- oder Pyridylgruppe bedeutet, wovon jede substituiert sein kann, R1 Wasserstoff darstellt.
1-Benzoyl-3-[1 -(naphth-1-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(4-isopropylbenzyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(5,6,7,8-tetrahydronaphth-2-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(3,4-dimethylbenzyl)-piperid-4-yl]-harnstoff,
1 -Benzoyl-3-[1 -(indan-5-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-{ 1-[ 1-(naphth-2-yl)-äthyl]piperid-4-yl}-harnstoff,
1-Benzoyl-3-[1-(4-äthylkbenzyl)-piperid-4-yl]-harnstoff,
3-Benzoyl-1-[ 1-(1,4-benzodioxan-6-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(6-methoxynaphth-2-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoy)-3-[1-(2-[naphth-1-yloxy]-äthyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(3,4-dibrombenzyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(4-n-propoxybenzyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(2-[naphth-2-yl]-äthyl)-piperid-4-yl]harnstoff,
1-Benzoyl-3-[1-( 1-[naphth-2-yl]-propyl)-piperid-4-yl]-harnstoff
oder ein pharmazeutisch annehmbares Säureadditions- oder quaternäres Ammoniumsalz hievon.
1-(3,4-Dimethylbenzoyl)-3-[1-(naphth-2-ylmethyl)-piperid-4-yl]-harnstoff,
1-(4-Methoxybenzoyl)-3-[ 1-(naphth-2-ylmethyl)-piperid-4-yl]harnstoff,
1-(4-Fluorbenzoyl)-3-[1-(naphth-2-ylmethyl)-piperid-4-yl]-harnstoff und
1-(4-Nitrobenzoyl)-3-[ 1-(naphth-2-ylmethyll-piperid-4-yl]-harnstoff
oder ein pharmazeutisch annehmbares Säureadditions- oder quaternäres Ammoniumsalz hievon.
(a) eine Verbindung der Formel (II)
mit einer Verbindung der Formel (III)
in welchen Formeln die strichlierte Linie, n, Ar, X, Y, Z, R, R1, R2, R3 und R9 wie in Anspruch 1 definiert sind und W eine abspaltbare Gruppe ist, umgesetzt wird,
oder
(b) eine Verbindung der Formel (IV)
mit einer Verbindung der Formel
in welchen Formeln n, Ar, Y, Z, R, R1, R2 und R9 wie in Anspruch 1 definiert sind und X 0 oder S bedeutet, zu einer Verbindung der
Formel (1), worin R3 Wasserstoff bedeutet, umgesetzt wird, oder
(c) eine Verbindung der Formel (IV), wie oben definiert, mit einer Verbindung der
Formel
worin X 0 oder S bedeutet und R, R3 und Z wie in Anspruch 1 definiert sind, umgesetzt wird, oder
(d) eine Verbindung der Formel
worin n, Ar, X, Y, R1, R2, R3 und R9 wie in Anspruch 1 definiert sind, mit einem Acylierungsmittel, das die Gruppe ―COR
enthält, zu einer entsprechenden Verbindung der Formel (I), worin Z ―CO― bedeutet,
umgesetzt wird, oder
(e) eine Verbindung der Formel (VII) oder (VIII)
oder
worin n, Ar, X, Y, Z, R, R1, R2 und R9 wie in Anspruch 1 definiert sind und B- ein Anion ist, reduziert wird, oder
(f) eine Verbindung der Formel (IX)
worin, n, Ar, Y, R2 und R9 wie in Anspruch 1 definiert sind, mit einer Verbindung der Formel (11), wie oben
definiert, worin X die Bedeutung 0 hat, in Anwesenheit eines Nickelkatalysators umgesetzt
wird, oder
(g) eine Verbindung der Formel (X)
worin die strichlierte Linie, Ar, Y, Z, R, R1, R2 und R3 wie in Anspruch 1 definiert sind und B ein Anion darstellt, X die Bedeutung =0 hat,
n=1 ist und R10 eine organische quaternisierende Gruppe darstellt, unter geeigneten Bedingungen zur
Entfernung der Gruppe R10 behandelt wird, wobei eine entsprechende Verbindung der Formel (I) erhalten wird,
oder
(h) eine Verbindung der Formel (XII)
worin die strichlierte Linie, n, R, R1, R2, R3, R9, X und Z wie in Anspruch 1 definiert sind und Hal Halogen bedeutet, mit einer Verbindung
der Formel
worin Ar wie in Anspruch. definiert ist, zu einer Verbindung der Formel (I), worin
Y ―O― bedeutet, umgesetzt wird, oder
(i) eine Verbindung der Formel (I) mit einer reaktionsfähigen Substituentengruppe in eine Verbindung der Formel (I) mit einer anderen Substituentengruppe überführt wird, oder
(j) eine basische Verbindung der Formel (1) in ein Säureadditions- oder quaternäres Ammoniumsalz oder ein Säureadditionssalz einer Verbindung der Formel (I) in die freie Basenform überführt wird.
und deren Säureadditions- und quaternären Ammoniumsalzen, worin die strichlierte Linie eine gegebenenfalls vorhandene Bindung darstellt, Ar ein Ringsystem der Formel
ist, worin Q die Bedeutung O, S, ―CR7=CR8― ―N=CR8― und N=N― hat; R4, R5 und R7 und R8, wenn vorhanden, jeweils Wasserstoff oder ein Substituent ausgewählt aus Halogen, nied.-Alkyl, Alkenyl mit 2 bis 6 C-Atomen, nied.Alkoxy, N02, NH2, Halogen-nied.alkyl, Hydroxy-nied.alkyl, Amino-nied.alkyl, Mono- oder Di-nied.alkylamino, nied.Alkylcarbonylamino, Ureido, nied.Alkylsulfonamido, Di-nied.alkyl- sulfonylamino, nied.Alkoxycarbonyl, Cyano, CONH2 und Hydroxy sind; und weiterhin entweder R4 und R5, wenn sie benachbart sind, oder R6 und R8, wenn sie benachbart sind, zusammen mit den C-Atomen, an die sie gebunden sind, auch einen kondensierten 5- oder 6-gliedrigen carbocyclischen oder heterocyclischen Ring bilden, der gegebenenfalls einen oder mehreren Substituenten, wie oben definiert, trägt; R ein Aryl- oder Heteroarylrest ist, jeweils gegebenenfalls substituiert durch einen oder mehrere Substituenten, wie oben für R4 definiert, oder R einen Cycloalkylrest mit 5 bis 7 C-Atomen darstellt; RI, R2, R3 und R9 jeweils Wasserstoff oder nied.Alkyl bedeuten; n=Null oder 1 ist; X =O oder =S darstellt; Y -0- oder eine Direktbindung bedeutet und Z ―CO― oder ―CH2― ist, wobei der Ausdruck "nied.", der für Alkyl oder Alkoxy verwendet wird, bedeutet, daß derartige Gruppen 1 bis 6 C-Atome enthalten, und der Ausdruck "Heteroaryl" eine einwertige aromatische heterocyclische Gruppe bezeichnet, in der das Heteroatom aus Sauerstoff, Stickstoff und Schwefel ausgewählt ist; mit den Maßgaben, daß, (i) wenn Ar unsubstituiertes Phenyl ist und R9 Wasserstoff darstellt, Y ―O― ist, und (ii) wenn Z ―CH2― ist und Ar eine Phenyl- oder Pyridylgruppe bedeutet, wovon jede substituiert sein kann, R1 Wasserstoff darstellt, dadurch gekennzeichnet, daß
(a) eine Verbindung der Formel (II)
mit einer Verbindung der Formel (III)
in welchen Formeln die strichlierte Linie, n, Ar, X, Y, Z, R, R1, R2, R3 und R9 wie oben definiert sind und W eine abspaltbare Gruppe ist, umgesetzt wird, oder
(b) eine Verbindung der Formel (IV)
mit einer Verbindung der Formel
in welchen Formeln n, Ar, Y, Z, R, R1, R2 und R9 wie oben definiert sind und X 0 oder S bedeutet, zu einer entsprechenden Verbindung
der Formel (1), worin R3 Wasserstoff bedeutet, umgesetzt wird, oder
(c) eine Verbindung der Formel (IV), wie oben definiert, mit einer Verbindung der
Formel
worin X 0 oder S bedeutet und R, R3 und Z wie oben definiert sind, umgesetzt wird, oder
(d) eine Verbindung der Formel
worin n, Ar, X, Y, R1, R2, R3 und R9 wie oben definiert sind, mit einem Acylierungsmittel, das die Gruppe ―COR enthält
zu einer entsprechenden Verbindung der Formel (I), worin Z ―CO― bedeutet, umgesetzt
wird, oder
(e) eine Verbindung der Formel (VII) oder (VIII)
oder
worin n, Ar, X, Y, Z, R, R1, R2 und R9 wie oben definiert sind und B⊖ ein Anion ist, reduziert wird, oder
(f) eine Verbindung der Formel (IX)
worin n, Ar, Y, R2 und R9 wie oben definiert sind, mit einer Verbindung der Formel (II), wie oben definiert,
worin X die Bedeutung 0 hat, in Anwesenheit eines Nickelkatalysators umgesetzt wird,
oder
(g) eine Verbindung der Formel (X)
worin die strichlierte Linie, Ar, Y, Z, R, R1, R2, R3 und B wie oben definiert sind, X die Bedeutung =0 hat, n=1 ist und R10 eine organische quaternisierende Gruppe darstellt, unter geeigneten Bedingungen zur
Entfernung der Gruppe R10 behandelt wird, wobei eine entsprechende Verbindung der Formel (I) erhalten wird,
oder
(h) eine Verbindung der Formel (XII)
worin die strichlierte Linie, n, R, R1, R2, R3, R9, X und Z wie oben definiert sind und Hal Halogen bedeutet, mit einer Verbindung der
Formel
worin Ar wie oben definiert ist, zu einer Verbindung der Formel (I), worin Y -0- bedeutet,
umgesetzt wird, oder
(i) eine Verbindung der Formel (I) mit einer reaktionsfähigen Substituentengruppe in eine Verbindung der Formel (I) mit einer anderen Substituentengruppe überführt wird, oder
(j) eine basische Verbindung der Formel (I) in ein Säureadditions- oder quaternäres Ammoniumsalz oder ein Säureadditionssalz einer Verbindung der Formel (I) in die freie Basenform überführt wird.
1-Benzoyl-3-[1-(naphth-1-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(4-isopropylbenzyl]-piperid-4-yl]harnstoff,
1-Benzoyl-3-[1-(5,6,7,8-tetrahydronaphth-2-ylmethyl)-piperid-4-yl]-hamstoff,
1-Benzoyl-3-[1-(3,4-dimethylbenzyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(indan-5-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-{1-[1-(naphth-2-yl)-äthyl]-piperid-4-yl}-harnstoff,
1-Benzoyl-3-[1-(4-äthylbenzyl)-piperid-4-yl]-harnstoff,
3-Benzoyl-1-[1-(1,4-benzodioxan-6-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(6-methoxynaphth-2-ylmethyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(2-[naphth-1-yloxy]-äthyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(3,4-dibrombenzyl)-piperid-4-yl]-harnstoff,
1-Benzoy)-3-[1-(4-n-propoxybenzyl)-piperid-4-yl]-harnstoff,
1-Benzoyl-3-[1-(2-[naphth-2-yl]-äthyl)-piperid-4-yl]harnetoff oder
1-Benzoyl-3-[1-(1-[naphth-2-yl]-propyl)-piperid-4-yl]-harnstoff ist.
1-(3,4-Dimethylbenzoyl)-3-[1-(naphth-2-ylmethyl)-piperid-4-yl]-harnstoff,
1-(4-Methoxybenzoyl)-3-[ 1-(naphth-2-ylmethyl)-piperid-4-yl]-harnstoff,
1-(4-Fluorbenzoyl)-3-[1-(naphth-2-ylmethyl)-piperid-4-yll-harnstoff und
1-(4-Nitrobenzoyl)-3-[ -(naphth-2-ylmethyl)-piperid-4-yl]-harnstoff
oder ein pharmazeutisch annehmbares Säureadditions- oder quaternäres Ammoniumsalz hievon ist.
et ses sels d'addition d'acides et sels d'ammonium quaternaire, formule dans laquelle le segment en traits interrompus représente une liaison facultative, Ar représente un noyau de formule
où Q représente O, S, ―CR7=CR8―, ―N=CR8― et ―N=N―; R4, R5 et R6, et R7 et R8 lorsqu'ils sont présents, représentent chacun l'hydrogène ou un substituant choisi entre un halogène, un groupe alkyle inférieur, alcényle ayant 2 à 6 atomes de carbone, alkoxy inférieur, NO2, NH2, halogénalkyle inférieur, hydroxyalkyle inférieur, aminoalkyle inférieur, (mono- ou dialkyle inférieur) amino, (alkyle inférieur) carbonylamino, uréido, (alkyle inférieur) sulfamido, di-(alkyle inférieur)-sulfonylamino, (alkoxy inférieur)-carbonyle, cyano, CONH2 et hydroxy; et en outre, R4 et R5 lorsqu'ils sont adjacents ou R6 et R8 lorsqu'ils sont adjacents, représentent aussi, conjointement avec les atomes de carbone auxquels ils sont liés, un noyau carbocyclique ou hétérocyclique pentagonal ou hexagonal condensé, portant éventuellement on ou plusieurs substituants tels que définis ci-dessus; R est un radical aryle ou hétéro-aryle dont chacun est éventuellement substitué par un ou plusieurs substituants tels que définis ci-dessus pour R4, ou bien R est un radical cycloalkyle contenant 5 à 7 atomes de carbone; R1, R2, R3 et R9 représentent chacun l'hydrogène ou un groupe alkyle inférieur; n a la valeur O ou 1; X représente =O ou =S; Y représente ―O― ou une liaison directe et Z représente ―CO― ou ―CH2― , le terme "inférieur" utilisé pour qualifier un groupe alkyle ou alkoxy signifiant de tels groupes qui contiennent 1 à 6 atomes de carbone, et le terme "hétéroaryle" signifiant un groupe hétérocyclique aromatique monovalent dont l'hétéro- atome est choisi entre oxygène, azote et soufre; sous réserve que (i) lorsque Ar est un groupe phényle non substitué et que R9 est l'hydrogène, Y représente alors -0-, et que (ii) lorsque Z représente ―CH2― et que Ar représente un groupe phényle ou pyridyle, l'un et l'autre pouvant être substitués, R1 représente alors l'hydrogène.
1-benzoyl-3-[1-(napht-1-ylméthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1 -(4-isopropyibenzyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(5,6,7,8-tétrahydronapht-2-ylméthyl)-pipérid-4-yl]urée;
1-benzoyl-3-[1 -(3,4-diméthyibenzyl)pipérid-4-yl]urée;
1-benzoyl-3-[1 -(indane-5-ylméthyl)pipérid-4-yl]urée;
1-benzoyl-3-{ 1-[1-(napht-2-yl)éthyl]-pipérid-4-yl}urée;
1-benzoyl-3-[1-(4-éthylbenzyl)pipérid-4-yl]urée;
3-benzoyl-1-[1-(1,4-benzodioxane-6-ylméthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(6-méthoxynapht-2-ylméthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(2-napht-1-yloxyléthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(3,4-dibromobenzyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(4-n-propoxybenzyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(2-[napht-2-yl]éthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1 -(1 -[napht-2-yl]propyl)pipérid-4-yl]urée,
ou un sel d'addition d'acide ou un sel d'ammonium quaternaire pharmaceutiquement acceptable de ces composés.
la 1-(3,4-diméthylbenzoyl)-3-[1-(napht-2-ylméthyl)-pipérid-4-yl]urée;
la 1-(4-méthoxybenzoyl)-3-[1 -(napht-2-ylméthyl)pipérid-4-yl]urée;
la 1-(4-fluorobenzoyl)-3-[1-(napht-2-ylméthyl)pipérid-4-yl]-urée; et
la 1-(4-nitrobenzoyl)-3-[1-(napht-2-ylméthyl)pipérid-4-yl]-urée,
ou un sel d'addition d'acide ou un sel d'ammonium quaternaire pharmaceutiquement acceptable de ce composé.
(a) un composé de formule Il
est amené à réagir avec un composé de formule III
formules dans lesquelles le segment en traits interrompus, n, Ar, X, Y, Z, R, R1, R2, R3 et R9 ont les définitions données dans la revendication 1, et W représente un groupe partant;
ou bien
b) un composé de formule (IV)
est amené à réagir avec un composé de formule
formules dans lesquelles n, Ar, Y, Z, R, R1, R2 et R9 ont les définitions données dans la revendication 1, et X représente O ou S pour
former un composé correspondant de formule I dans laquelle R3 est l'hydrogène,
ou bien
(c) un composé de formule IV telle que définie ci-dessus est amené à réagir avec un
composé de formule
dans laquelle X représente 0 ou S et R, R3 et Z ont les définitions données dans la revendication 1,
ou bien
(d) un composé de formule VI
dans laquelle n, Ar, X, Y, R1, R2, R3 et R9 sont tels que définis dans la revendication 1, est acylé avec un agent acylant contenant
le groupe ―COR pour former un composé correspondant de formule I dans laquelle Z représente
-CO-,
ou bien
(e) un composé de formule VII ou VIII
ou
où n, Ar, X, Y, Z, R, R1, R2, R3 et R9 sont tels que définis dans la revendication 1, et B- est un anion, est réduit, ou bien
(f) un composé de formule IX
dans laquelle n, Ar, Y, R2 et R9 sont tels que définis dans la revendication 1, est amené à réagir avec un composé
de formule II telle que définie ci-dessus, dans laquelle X représente O, en présence
d'un catalyseur au nickel,
ou bien
(g) un composé de formule X
dans laquelle le segment en traits interrompus, Ar, Y, Z, R, R1, R2 et R3 sont tels que définis dans la revendication 1, et B est un anion, X représente =O,
n est égal à 1 et R10 est un groupe organique quaternisant, est traité dans des conditions favorables à
l'élimination du groupe R10 pour donner un composé correspondant de formule I,
ou bien
(h) un composé de formule XII
dans laquelle le segment en traits interrompus, n, R, R1, R2, R3, R9, X et Z sont tels que définis dans la revendication 1 et hal représente un halogène,
est amené à réagir avec un composé de formule:
dans laquelle Ar est tel que défini dans la revendication 1 pour donner un composé
de formule I dans laquelle Y représente -0-, ou bien
(i) un composé de formule I portant un groupe substituant réactif est converti en un composé de formule I portant un groupe substituant différent,
ou bien
(j) un composé basique de formule I est converti en un sel d'addition d'acide ou un sel d'ammonium quaternaire ou bien un sel d'addition d'acide d'un composé de formule I est converti en la base libre.
et de sels d'addition d'acides et d'ammonium quaternaire de ce composé, formule dans laquelle le segment en traits interrompus représente une liaison facultative, Ar représente un noyau de formule
où Q représente O, S, ―CR7=CR8―, ―N=CR8― et ―N=N―; R4, R5 et R6, et R7 et R8 lorsqu'ils sont présents, représentent chacun l'hydrogène ou un substituant choisi entre un halogène, un groupe alkyle inférieur, alcényle ayant 2 à 6 atomes de carbone, alkoxy inférieur, NO2, NH2, halogénalkyle inférieur, hydroxyalkyle inférieur, aminoalkyle inférieur, (mono- ou dialkyle inférieur) amino, (alkyle inférieur) carbonylamino, uréido, (alkyle inférieur) sulfamido, di-(alkyle inférieur)-sulfonylamino, (alkoxy inférieur)-carbonyle, cyano, CONH2 et hydroxy; et en outre, R4 et R5 lorsqu'ils sont adjacents ou R6 et R8 lorsqu'ils sont adjacents, représentent aussi, conjointement avec les atomes de carbone auxquels ils sont liés, un noyau carbocyclique ou hétérocyclique pentagonal ou hexagonal condensé, portant éventuellement un ou plusieurs substituants tels que définis ci-dessus; R est un radical aryle ou hétéro-aryle dont chacun est éventuellement substitué par un ou plusieurs substituants tels que définis ci-dessus pour R4, ou bien R est un radical cycloalkyle contenant 5 à 7 atomes de carbone; R1, R2, R3 et R9 représentent chacun l'hydrogène ou un groupe alkyle inférieur; n a la valeur 0 ou 1; X représente =0 ou =S; Y représente ―O― ou une liaison directe et Z représente ―CO― ou ―CH2―, le terme "inférieur" utilisé pour qualifier un groupe alkyle ou alkoxy signifiant de tels groupes qui contiennent 1 à 6 atomes de carbone, et le terme "hétéroaryle" signifiant un groupe hétérocyclique aromatique monovalent dont l'hétéro- atome est choisi entre oxygène, azote et soufre; sous réserve que (i) lorsque Ar est un groupe phényle non substitué et que R9 est l'hydrogène, Y représente alors -0-, et que (ii) lorsque Z représente ―CH2― et que Ar représente un groupe phényle ou pyridyle, l'un et l'autre pouvant être substitués, R1 représente alors l'hydrogène.
caractérisé en ce que:
(a) un composé de formule Il
est amené à réagir avec un composé de formule III
formules dans lesquelles le segment en traits interrompus, n, Ar, X, Y, Z, R, R1, R2, R3 et R9 ont les définitions données ci-dessus, et W représente un groupe partant;
ou bien
(b) un composé de formule (IV)
est amené à réagir avec un composé de formule
formules dans lesquelles n, Ar, Y, Z, R, R1, R2 et R9 ont les définitions données ci-dessus, et X représente O ou S pour former un composé
correspondant de formule I dans laquelle R3 est l'hydrogène, ou bien
(c) un composé de formule IV tel que défini ci-dessus est amené à réagir avec un composé
de formule
dans laquelle X représente 0, S ou NH et R, R3 et Z ont les définitions données ci-dessus, ou bien
(d) un composé de formule VI
dans laquelle n, Ar, X, Y, R1, R2, R3 et R9 sont tels que définis ci-dessus, est acylé avec un agent acylant contenant le groupe
―COR pour former un composé correspondant de formule I dans laquelle Z représente
-CO-,
ou bien
(e) un composé de formule VII ou VIII
ou
où n, Ar, X, Y, Z, R, R1, R2, R3 et R9 sont tels que définis ci-dessus, et B⊖ est un anion, est réduit, ou bien
(f) un composé de formule IX
dans laquelle n, Ar, Y, R2 et R9 sont tels que définis ci-dessus, est amené à réagir avec un composé de formule Il
telle que définie ci-dessus, dans laquelle X représente 0, en présence d'un catalyseur
au nickel,
ou bien
(g) un composé de formule X
dans laquelle Ar, Y, Z, R, R1, R2 et R3 et B sont tels que définis ci-dessus, X représente =0; n est égal à 1 et R10 est un groupe organique quaternisant, est traité dans des conditions favorables à
l'élimination du groupe R10 pour donner un composé correspondant de formule I,
ou bien
(h) un composé de formule XII
dans laquelle le segment en traits interrompus, n, R, R1, R2, R3, R9, X et Z sont tels que définis ci-dessus et hal représente un halogène, est amené
à réagir avec un composé de formule:
dans laquelle Ar est tel que défini ci-dessus pour donner un composé de formule I
dans laquelle Y représente -0-,
ou bien
(i) un composé de formule I portant un groupe substituant réactif est converti en un composé de formule I portant un groupe substituant différent,
ou bien
(j) un composé basique de formule I est converti en un sel d'addition d'acide ou un sel d'ammonium quaternaire ou bien un sel d'addition d'acide d'un composé de formule I est converti en la base libre.
1-benzoyl-3-[1-(napht-1-ylméthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1 -(4-isopropylbenzyl)pipérid-4-yl]urée:
1-benzoyl-3-[1-(5,6,7,8-tétrahydronapht-2-ylméthyl)-pipérid-4-yl]urée;
1-benzoyl-3-[1-(3,4-diméthylbenzyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(indane-5-ylméthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-[1-(napht-2-yl)éthyl]-pipérid-4-yl]urée;
1-benzoyl-3-[1-(4-éthylbenzyl)pipérid-4-yl]urée;
3-benzoyl-1-[1-(1,4-benzodioxane-6-ylméthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(6-méthoxynapht-2-ylméthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(2-napht-1-yloxyléthyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(3,4-dibromobenzyl)pipérid-4-yl]urée;
1-benzoyl-3-[1 -(4-n-propoxybenzyl)pipérid-4-yl]urée;
1-benzoyl-3-[1-(2-[napht-2-yl]éthyl)pipérid-4-yl]urée; ou
1-benzoyl-3-[1-( 1-[napht-2-yl]propyl)pipérid-4-yl]urée.
la 1-(3,4-diméthylbenzoyl)-3-[1-(napht-2-ylméthyf)-pipérid-4-yl]urée;
la 1-(4-méthoxybenzoyl)-3-[1-(napht-2-ylméthyl)pipérid-4-yl]urée;
la 1-(4-fluorobenzoyl)-3-[1-(napht-2-ylméthyl)pipérid-4-yl]urée; et
la 1-(4-nitrobenzoyl)-3-[1-(napht-2-ylméthyl)pipérid-4-yl]-urée,
ou un sel d'addition d'acide ou un sel d'ammonium quaternaire pharmaceutiquement acceptable de ce composé.